Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

Patrick J. Grohar, Suntae Kim, Guillermo O. Rangel Rivera, Nirmalya Sen, Sara Haddock, Matt L. Harlow, Nichole K. Maloney, Jack Zhu, Maura O'Neill, Tamara L. Jones, Konrad Huppi, Magdalena Grandin, Kristen Gehlhaus, Carleen A. Klumpp-Thomas, Eugen Buehler, Lee J. Helman, Scott E. Martin, Natasha J. Caplen

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

Original languageEnglish (US)
Pages (from-to)598-610
Number of pages13
JournalCell Reports
Volume14
Issue number3
DOIs
StatePublished - Jan 26 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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